Diffuse large B-cell lymphomas (DLBCLs), the most common lymphoid malignancies, are clinically and genetically heterogeneous disorders. Although DLBCL is a chemo-responsive tumor, many patients will not be cured with conventional therapy. Several genetic abnormalities (t(14;18), t(3;v), t(8;14), FAS death domain deletion) have been identified in subsets of DLBCLs. However, the majority of DLBCLs lack these lesions suggesting that additional pathogenetic mechanisms remain to be defined. To elucidate bases of clinical and molecular heterogeneity in DLBCL, we used gene expression profiles and targeted genetic analyses to develop comprehensive molecular signatures of tumors that share similar features and rely upon common survival pathways. In the first funding period, risk-related pathways were identified and credentialed in vitro and targeted pathway inhibitors were evaluated in preclinical and clinical trials. In addition, robust and highly reproducible LBCL subtypes (primary MLBCL and DLBCL consensus clusters) were identified, validated in independent datasets and preliminarily characterized with respect to underlying pathogenetic mechanisms. The molecular signature of MLBCL was strikingly similar to that of classical Hodgkin's lymphoma (cHL), of interest because these diseases share clinical and genetic features including constitutive NFxB activation. The 3 distinct subtypes of DLBCL (OxPhos, BCR, Host Response [HR]) were independent of prior distinctions (such as cell-of-origin) and associated with different genetic signatures. OxPhos tumors had increased expression of genes regulating mitochondrial function, electron transport, apoptosis and proteasomal degradation and more frequent t(14;18). BCR DLBCLs had increased expression of DNA repair genes, BCR signaling cascade components and B-cell specific transcription factors and more commonly had t(3;v). HR tumors had a brisk host inflammatory/immune infiltrate, including increased numbers of tumor-infiltrating lymphocytes (TILs) and immunohistochemically defined CD2+ and CD3+ T-cells and GILT+ interdigitating dendritic cells. HR tumors resembled the provisional (WHO) DLBCL subtype, T/HR BCL, lacked the above-mentioned genetic abnormalities and had evidence of increased NFKB activation. In this competitive renewal, we propose to build on the previous studies with the following specific aims: 1) Elucidate pathogenetic mechanisms associated with the newly identified DLBCL subtypes and primary MLBCL; 2) Characterize the biological signatures of the DLBCL subtypes and primary MLBCL; and 3) Develop methods to predict sensitivity and analyze response to rational target inhibitors. Relevance of research to public health. DLBCLs are the most common malignant lymphoid tumors. These proposed studies will increase our diagnostic accuracy, provide insights into the causes of these common cancers and identify new possible therapeutic targets.